Using either Amyotrophic Lateral Sclerosis or Spinal Muscular Atrophy as an example (a) discuss the main genetic causes of the disease (50 %) and (b) describe the current approved treatment options available (50 %).

What is amyotrophic lateral sclerosis and how does it affect the nervous system? (1.1)

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder characterised by the selective loss of upper and lower motor neurons.

How is ALS clinically classified, and what proportions do these forms represent? (1.2)

Clinically, ALS is classified into familial ALS (FALS), accounting for approximately 10% of cases, and sporadic ALS (SALS), which comprises the remaining majority.

How have advances in human genetics altered the traditional distinction between familial and sporadic ALS? (1.3)

However, advances in human genetics have increasingly blurred this distinction, revealing that genetic factors contribute across the ALS spectrum.

How is the genetic architecture of ALS characterised? (1.4)

The genetic architecture of ALS is highly heterogeneous, ranging from highly penetrant Mendelian mutations to combinations of risk-conferring variants.

Why has genetic understanding been important for ALS therapeutic development? (1.5)

Importantly, this genetic understanding has directly informed the development of targeted therapeutic strategies, marking a shift towards precision medicine in a disease historically considered untreatable.

What is the most common genetic cause of ALS? (2.1)

The most common genetic cause of ALS is a GGGGCC hexanucleotide repeat expansion in C9orf72.

How does the C9orf72 repeat expansion contribute to ALS pathology? (2.2)

This mutation contributes to ALS through multiple converging mechanisms.

What is the first pathogenic mechanism caused by C9orf72 repeat expansion? (2.3)

First, haploinsufficiency results in reduced expression of the normal C9orf72 protein, which impairs autophagy, vesicle trafficking and immune regulation making motor neurones more vulnerable to stress and degeneration.

How do repeat-containing RNAs contribute to ALS in C9orf72 mutations? (2.4)

Second, repeat-containing RNA forms nuclear foci that sequester RNA-binding proteins, disrupting RNA metabolism.

What toxic products arise from repeat-associated non-ATG translation in C9orf72 ALS? (2.5)

Third, repeat-associated non-ATG translation generates toxic dipeptide repeat proteins that accumulate and impair proteostasis.

What do these mechanisms collectively illustrate about ALS pathogenesis? (2.6)

Together, these mechanisms illustrate how a single mutation can drive disease through parallel pathological pathways.

What was the first genetic cause of ALS to be identified? (2.7)

Mutations in SOD1 were the first genetic cause of ALS to be identified.

How do SOD1 mutations cause ALS? (2.8)

Importantly, these missense mutations do not cause disease through loss of antioxidant activity but instead through a toxic gain-of-function mechanism involving protein misfolding, aggregation, and prion-like propagation between cells.

What do TARDBP and FUS mutations reveal about ALS disease mechanisms? (2.9)

Mutations in TARDBP (encoding TDP-43) and FUS further highlight the central role of RNA-binding proteins in ALS.

What cellular consequences result from TARDBP and FUS mutations? (2.10)

These mutations lead to loss of normal nuclear function, including defects in RNA splicing, alongside cytoplasmic aggregation.

Why is TDP-43 pathology considered a unifying hallmark of ALS? (2.11)

Notably, TDP-43 pathology is observed in over 97% of ALS cases, including most sporadic disease, making it a unifying pathological hallmark.

How is sporadic ALS now understood in terms of genetic influence? (3.1)

Sporadic ALS is increasingly recognised as genetically influenced rather than non-genetic.

What genetic features are found in some sporadic ALS cases? (3.2)

Some SALS cases carry rare variants in classical FALS genes with incomplete penetrance.

What is oligogenic inheritance in sporadic ALS? (3.3)

Others reflect oligogenic inheritance, where multiple moderate-risk variants—such as those in ATXN2, NEK1, or C21orf2—combine to cross a pathogenic threshold.

What have genome-wide association studies revealed about ALS risk? (3.4)

In addition, genome-wide association studies have identified common risk variants, including loci such as UNC13A, that subtly increase lifetime ALS risk.

What overall genetic model of ALS do these findings support? (3.5)

These findings indicate that ALS genetics exists on a spectrum rather than as a strict familial versus sporadic division.

What role does riluzole play in ALS treatment? (4.1)

Riluzole remains a cornerstone of ALS therapy.

What is the proposed mechanism of action of riluzole? (4.2)

It is thought to reduce glutamatergic excitotoxicity, although its precise mechanism remains incompletely defined.

What clinical benefit does riluzole provide to ALS patients? (4.3)

Clinically, riluzole confers a modest survival benefit of approximately three months, highlighting the limited efficacy of early-generation treatments.

Why does riluzole provide only a modest survival benefit in patients with ALS? 4.4

Its modest effect likely results from treatment beginning after substantial motor‑neuron loss, underscoring the need for earlier diagnosis and more potent agents

What is edaravone and why was it approved for ALS? (4.4)

Edaravone is a free radical scavenger approved on the basis of its antioxidant properties.

What limitations are associated with edaravone therapy? (4.5)

While some trials demonstrated slowed functional decline in selected patient populations, its overall efficacy remains debated, and its intravenous administration imposes a significant treatment burden.

Why does the clinical uptake of edaravone vary across healthcare systems? 4.6

Its restricted benefit and delivery challenges mean uptake varies widely across healthcare systems. 

What type of therapeutic approach is Relyvrio (AMX0035)? (4.6)

Relyvrio (AMX0035) represents a more recent, multi-target approach.

What are the components and mechanisms of action of Relyvrio? (4.7)

It combines sodium phenylbutyrate, which modulates endoplasmic reticulum stress, with taurursodiol, which stabilises mitochondrial function.

What were the key findings of the CENTAUR trial for Relyvrio? (4.8)

The CENTAUR trial demonstrated slowed functional decline and improved survival, although debate remains regarding the relative contribution of each component.

What is the most significant recent advance in ALS therapeutics? (5.1)

The most significant recent advance in ALS therapeutics is the approval of tofersen (Qalsody), an antisense oligonucleotide targeting SOD1.

How does tofersen reduce mutant SOD1 protein levels? (5.2)

Tofersen binds SOD1 mRNA, promoting its degradation via RNase H and reducing synthesis of mutant SOD1 protein.

What biomarker effects were observed in the VALOR trial of tofersen? (5.3)

In the VALOR trial, tofersen produced robust reductions in CSF SOD1 levels and neurofilament biomarkers of neurodegeneration, although clinical efficacy endpoints were more modest.

Why was tofersen approved despite modest clinical outcomes? (5.4)

This led to approval based on biomarker outcomes, establishing a treat-to-target paradigm in ALS and marking the first gene-specific therapy for the disease.

What additional gene-targeted approaches are under investigation for ALS? (5.5)

Parallel efforts are underway to target C9orf72 repeat expansions using antisense oligonucleotides designed to degrade toxic repeat-containing RNA, although these approaches remain investigational.

How does ALS exemplify the relationship between genetics and therapy development? (6.1)

ALS exemplifies the convergence of genetic complexity and therapeutic innovation.

How has the ALS field evolved from early genetic discoveries to modern therapies? (6.2)

From the discovery of SOD1 mutations to the clinical deployment of SOD1-targeted antisense therapy, the field has transitioned from descriptive genetics to mechanism-driven intervention.

Why is genetic stratification now central to ALS management? (6.3)

Genetic stratification is now central to ALS management, not merely explanatory.

What future strategies are expected to yield the greatest therapeutic gains in ALS? (6.4)

Looking forward, the greatest therapeutic gains are likely to arise from combination strategies that pair gene-specific therapies with broader neuroprotective agents, as well as from pre-symptomatic treatment of mutation carriers.

What does the future trajectory of ALS treatment suggest about disease control? (6.5)

Together, these advances suggest that ALS is beginning to move from an inevitably fatal disorder towards a condition that may one day be biologically controllable.